Ophthalmic lens materials containing chromophores that absorb both UV and short wavelength visible light

ABSTRACT

Chromophores that absorb both UV and short wavelength visible light are disclosed. The chromophores are particularly suitable for use in intraocular lens materials.

This application claims priority to U.S. Provisional Application, U.S.Ser. No. 60/954,988 filed Aug. 9, 2007.

FIELD OF THE INVENTION

This invention is directed to chromophores. In particular, thisinvention relates to chromophores that absorb both UV and shortwavelength light.

BACKGROUND OF THE INVENTION

Many UV light absorbers are known as ingredients for polymeric materialsused to make ophthalmic lenses. UV absorbers are preferably covalentlybound to the polymeric network of the lens material instead of simplyphysically entrapped in the material to prevent the absorber frommigrating, phase separating or leaching out of the lens material. Suchstability is particularly important for implantable ophthalmic lenses,especially intraocular lenses (IOLs), where the leaching of the UVabsorber may present both toxicological issues and lead to the loss ofUV blocking activity in the implant.

Numerous copolymerizable benzatriazole, benzophenone and triazine UVabsorbers are known. Many of these UV absorbers contain conventionalolefinic polymerizable groups, such as methacrylate, acrylate,methacrylamide, acrylamide or styrene groups. Copolymerization withother ingredients in the lens materials, typically with a radicalinitiator, incorporates the UV absorbers into the resulting polymerchain. Incorporation of additional functional groups, on a UV absorbermay influence one or more of the UV absorber's UV absorbing properties,solubility or reactivity. If the UV absorber does not have sufficientsolubility in the remainder of the ophthalmic lens material ingredientsor polymeric lens material, the UV absorber may coalesce into domainsthat could interact with light and result in decreased optical clarityof the lens.

Examples of polymeric ophthalmic lens materials that incorporate UVabsorbers can be found in U.S. Pat. Nos. 5,290,892; 5,331,073 and5,693,095.

Likewise, copolymerizable short wavelength light absorbing chromophoresare known as ingredients for polymeric materials used to make ophthalmiclenses. Blue-light absorbing chromophores include those disclosed inU.S. Pat. Nos. 5,470,932 and 5,543,504.

In order to obtain polymeric lens materials that absorb both UV andshort wavelength visible light (e.g., 400-500 nm), it is common to addseparate UV-absorbing and short wavelength light-absorbing chromophoresto the polymeric materials. For example, the AcrySof® Natural IOLproduct, which is commercially available from Alcon Laboratories, Inc.,contains a UV absorber and a blue-light absorber.

Having a single chromophore that absorbs both UV and short wavelengthvisible light would be advantageous. Such a single chromophore wouldreduce the number of components that are added to a lens materialformulation and reduce disruption to the primary polymer chain structureproduced by the lens formulation's primary monomer constituents.

SUMMARY OF THE INVENTION

The present invention provides chromophores that absorb both UV andshort wavelength visible light. These chromophores are suitable for usein ophthalmic lenses, including contact lenses. They are particularlyuseful in implantable lenses, such as IOLs.

DETAILED DESCRIPTION OF THE INVENTION

Unless indicated otherwise, all ingredient amounts expressed inpercentage terms are presented as % w/w.

The chromophores of the present invention are represented by the formula

wherein

-   A=H or CH₃;-   X═O or NH;-   n=2-6;-   m=0-6;-   R¹═H, OH, C₁-C₄ alkyl, or C₁-C₄ alkoxy; and-   R²═H or OH.

A preferred chromophore of the present invention has

-   A=CH₃;-   X═O;-   n=2;-   m=0;-   R¹═H; and-   R²═H.

The synthesis of the chromophores of the present invention is describedbelow (Scheme 1). Aromatic alkyne (2) is synthesized in 2 steps from4-bromo-phenethyl alcohol. Sonogishira coupling of the aryl bromide withtrimethylsilylacetylene, followed by deprotection and esterificationwith methacryloyl chloride produces a methacrylate functionalized arylalkyne (2). Alternatively, esterification with 4-vinylbenzoic acid usingcarbodiimide coupling will produce a vinyl-functional chromophore. Theazo coupling product from 4-iodo-2-methylaniline with p-cresol isconverted to the aryl azide (4) by proline promoted CuI-catalyzedcoupling (Zhu, W.; Ma, D. Chem. Commun. 2004, 888). This is thencombined with an equimolar amount of aryl akyne (2) and a catalyticamount of CuBr to yield 1,2,3-triazole (5).

The chromophores of the present invention are particularly suitable foruse in IOLs. IOL materials will generally contain from 0.1 to 5% (w/w)of a chromophore of the present invention. Preferably, IOL materialswill contain from 0.5 to 3% (w/w) of a chromophore of the presentinvention. Such device materials are prepared by copolymerizing thechromophores of the present invention with other ingredients, such asdevice-forming materials and cross-linking agents.

Many device-forming monomers are known in the art and include bothacrylic and silicone-containing monomers among others. See, for example,U.S. Pat. Nos. 7,101,949; 7,067,602; 7,037,954; 6,872,793 6,852,793;6,846,897; 6,806,337; 6,528,602; and 5,693,095. In the case of IOLs, anyknown IOL device material is suitable for use in the compositions of thepresent invention. Preferably, the ophthalmic device materials comprisean acrylic or methacrylic device-forming monomer. More preferably, thedevice-forming monomers comprise a monomer of formula [II]:

where in formula [II]:

-   -   A is H, CH₃, CH₂CH₃, or CH₂OH;    -   B is (CH₂)_(m) or [O(CH₂)₂]_(z);    -   C is (CH₂)_(w);    -   m is 0-6;    -   z is 1-10;    -   Y is nothing, O, S, or NR′, provided that if Y is O, S, or NR′,        then B is (CH₂)_(m);    -   R′ is H, CH₃, C_(n′)H_(2n′+1) (n′=1-10), iso-OC₃H₇, C₆H₅, or        CH₂C₆H₅;    -   w is 0-6, provided that m+w≦8; and    -   D is H, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₆H₅, CH₂C₆H₅ or halogen.

Preferred monomers of formula [II] are those wherein A is H or CH₃, B is(CH₂)_(m), m is 1-5, Y is nothing or O, w is 0-1, and D is H. Mostpreferred are benzyl methacrylate; 2-phenylethyl methacrylate;4-phenylbutyl methacrylate; 5-phenylpentyl methacrylate;2-benzyloxyethyl methacrylate; and 3-benzyloxypropyl methacrylate; andtheir corresponding acrylates.

Monomers of formula [II] are known and can be made by known methods. Forexample, the conjugate alcohol of the desired monomer can be combined ina reaction vessel with methyl methacrylate, tetrabutyl titanate(catalyst), and a polymerization inhibitor such as 4-benzyloxy phenol.The vessel can then be heated to facilitate the reaction and distill offthe reaction by-products to drive the reaction to completion.Alternative synthesis schemes involve adding methacrylic acid to theconjugate alcohol and catalyzing with a carbodiimide or mixing theconjugate alcohol with methacryloyl chloride and a base such as pyridineor triethylamine.

Device materials generally comprise a total of at least about 75%,preferably at least about 80%, of device-forming monomers.

In addition to a chromophore of the present invention and adevice-forming monomer, the device materials of the present inventiongenerally comprise a cross-linking agent. The cross-linking agent usedin the device materials of this invention may be any terminallyethylenically unsaturated compound having more than one unsaturatedgroup. Suitable cross-linking agents include, for example: ethyleneglycol dimethacrylate; diethylene glycol dimethacrylate; allylmethacrylate; 1,3-propanediol dimethacrylate; 2,3-propanedioldimethacrylate; 1,6-hexanediol dimethacrylate; 1,4-butanedioldimethacrylate; CH₂═C(CH₃)C(═O)O—(CH₂CH₂O)_(p)—C(═O)C(CH₃)═CH₂ wherep=1-50; and CH₂═C(CH₃)C(═O)O(CH₂)_(t)O—C(═O)C(CH₃)═CH₂ where t=3-20; andtheir corresponding acrylates. A preferred cross-linking monomer isCH₂═C(CH₃)C(═O)O—(CH₂CH₂O)_(p)—C(═O)C(CH₃)═CH₂ where p is such that thenumber-average molecular weight is about 400, about 600, or about 1000.

Generally, the total amount of the cross-linking component is at least0.1% by weight and, depending on the identity and concentration of theremaining components and the desired physical properties, can range toabout 20% by weight. The preferred concentration range for thecross-linking component is 0.1-17% (w/w).

Suitable polymerization initiators for device materials containing achromophore of the present invention include thermal initiators andphotoinitiators. Preferred thermal initiators include peroxyfree-radical initiators, such as t-butyl (peroxy-2-ethyl)hexanoate anddi-(tert-butylcyclohexyl)peroxydicarbonate (commercially available asPerkadox® 16 from Akzo Chemicals Inc., Chicago, Ill.). Initiators aretypically present in an amount of about 5% (w/w) or less. The totalamount of initiator is customarily not included when determining theamounts of other ingredients.

IOLs constructed of the materials of the present invention can be of anydesign capable of being rolled or folded into a small cross section thatcan fit through a relatively smaller incision. For example, the IOLs canbe of what is known as a one piece or multipiece design, and compriseoptic and haptic components. The optic is that portion which serves asthe lens. The haptics are attached to the optic and hold the optic inits proper place in the eye. The optic and haptic(s) can be of the sameor different material. A multipiece lens is so called because the opticand the haptic(s) are made separately and then the haptics are attachedto the optic. In a single piece lens, the optic and the haptics areformed out of one piece of material. Depending on the material, thehaptics are then cut, or lathed, out of the material to produce the IOL.

In addition to IOLs, the materials of the present invention are alsosuitable for use in other ophthalmic devices, such as contact lenses,keratoprostheses, and corneal inlays or rings.

The invention will be further illustrated by the following examples,which are intended to be illustrative, but not limiting.

EXAMPLE 1 Synthesis of (1)

A flask is flushed with N₂ and charged with 4-bromo-phenethyl alcohol(20 mmol) and dissolved in 1/1 Et₃N/dioxane.Bis(triphenylphosphine)palladium(II) dichloride (PdCl₂(PPh₃)₂) (0.2mmol) is added, followed by 0.4 mmol of CuI. Trimethylsilylacetylene (24mmol) is added drop-wise to the reaction mixture. The reaction mixtureis stirred overnight under N₂. The solvent is removed under vacuum andthe resulting liquid is extracted by washing with ethyl ether. The ethylether extracts are combined and washed with H₂O, then dried overanhydrous sodium sulfate. The solvent is removed under vacuum and theproduct is purified by column chromatography. The purified product isplaced in a N₂-flushed flask and dissolved in methanol. Potassiumfluoride (65 mmol) is added and the reaction stirred under a N₂ blanketfor 16 h. The reaction mixture is poured into CH₂Cl₂ and extracted withH₂O, then dried over Na₂SO₄, filtered and the solvent is removed undervacuum. The resulting product is purified by column chromatography toyield 2-(4-ethynyl-phenyl)-ethanol (2).

EXAMPLE 2 Synthesis of (2)

A flask is flushed with N₂ and charged with 15 mmol of (2), 17 mmol oftriethylamine and CH₂Cl₂. The solution is cooled in an ice water bathand methacryloyl chloride (17 mmol) is added drop-wise with stirring.Once the addition is complete, the cold bath is removed and the reactionstirred for 16 hr under a N₂ blanket. The reaction mixture is washedwith 2 N HCl then washed with H₂O, and dried over anhydrous Na₂SO₄. Thesolvent is removed under vacuum and the resulting crude product ispurified by column chromatography to yield methacrylate (2).

EXAMPLE 3 Synthesis of (3)

A flask is charged with 100 mmol of boric acid followed by 6N HClsolution to adjust the reaction solution to a pH of 2. Once the saltdissolves, 20 mmol of 4-iodo-2-methylaniline is added to the reactionsolution, followed by enough ice to reduce solution temperature to 0° C.In a separate flask, 20 mmol of sodium nitrite (NaNO₂) is dissolved inice water. The NaNO₂ solution is added drop-wise with constant stirringto the 4-iodo-2-methylaniline solution. The pH of the reaction solutionis maintained by addition of 6N HCl. After the NaNO₂ solution additionis complete, ice is added to maintain the 0° C. reaction temperature. A3^(rd) flask is charged with 20 mmol of p-cresol, water and 2.5 N NaOH(20 mmol), which is then added drop wise to the ice cooled reaction withconstant stirring. The reaction mixture is allowed to stir for 15 min atpH 2.0-2.5. NaOH (2.5 N) is then added in small aliquots to the reactionsolution to increase the pH to 8.5. The reaction solution is allowed towarm to room temperature. Dibasic sodium phosphate solution (100 mmol)is added and the pH is adjusted to 6.0 with 6 N HCl. The product isfiltered, rinsed with ice water and air dried. The product is purifiedby column chromatography to yield2-(4-iodo-2-methyl-phenylazo)-4-methyl-phenol (3).

EXAMPLE 4 Synthesis of (4)

A flask is flushed with N₂ and charged with 10 mmol of (3), 12 mmol ofNaN₃, 1 mmol of CuI, 2 mmol of L-proline, 2 mmol of NaOH and DMSO. Thereaction flask is immersed in an oil bath and heated to 70° C. under aN₂ blanket for 10 hr. The reaction mixture is then allowed to cool toroom temperature and ethyl acetate is added and the solution is washedwith water. The organic layer is separated, and the aqueous layer isextracted with ethyl acetate. The combined organic layers are washedwith brine, dried over anhydrous Na₂SO₄, and the solvent is removedunder vacuum. The resulting product was purified by columnchromatography. to yield aryl azide (4).

EXAMPLE 5 Synthesis of (5)

A flask containing a PTFE coated stir bar is flushed with N₂ and chargedwith 15 mmol of aryl azide (4), 15 mmol of aryl acetylene (2),N,N-dimethylformamide, 3.0 mmol ofN,N,N′,N″,N″-pentamethyldiethylenetriamine, and 1.5 mmol of CuBr. Theflask is stirred 20 h at ambient temperature. The reaction mixture isthen exposed to air and purified by passing through a chromatographicalumina column. The eluent is collected and the solvent is removed undervacuum to yield product (5).

EXAMPLES 6-9 Copolymerization of a Chromophore with a Device-FormingMonomer

A vial is charged with ingredients as listed in Table 1 except for theinitiator. The solution is mixed thoroughly and de-gassed by bubblingwith N₂. The initiator is added and the solution is again mixedthoroughly. The solution is filtered through a 0.2 micron PTFE filterand transferred to polypropylene molds. The molds are heated in amechanical convection oven at 70° C. for 1 hr, then 110° C. for 2 hrs.The resulting copolymer samples are removed from the polypropylene moldsand extracted in refluxing acetone for at least 3 hr, then rinsed withfresh acetone and allowed to air dry. The extracted polymer is driedunder vacuum at 70° C. for at least 3 hr.

TABLE 1 Representative Copolymer Formulations Amount (% w/w) Ingredient6 7 8 9 PEA 65.0 80.0 0.0 65.0 PEMA 29.95 0.0 0.0 31.25 PBMA 0.0 0.082.15 0.0 HEMA 0.0 14.95 0.0 0.0 PEG(1000)DMA 0.0 0.0 15.0 0.0 EGDMA 0.00.0 1.0 0.0 BDDA 3.2 3.2 0.0 3.2 o-MTP 1.8 1.8 1.8 0.0 Chromophore (5)0.05 0.05 0.05 0.5 Perkadox ® 16S 1.0 1.0 1.0 1.0 PEA = 2-phenylethylacrylate PEMA = 2-phenylethyl methacrylate PBMA = 4-phenylbutylmethacrylate HEMA = 2-hydroxyethyl methacrylate PEG(1000)DMA =polyethylene glycol (1000) dimethacrylate EGDMA = ethylene glycoldimethacrylate BDDA = 1,4-butanediol diacrylate oMTP = o-methallylTinuvin P

This invention has been described by reference to certain preferredembodiments; however, it should be understood that it may be embodied inother specific forms or variations thereof without departing from itsspecial or essential characteristics. The embodiments described aboveare therefore considered to be illustrative in all respects and notrestrictive, the scope of the invention being indicated by the appendedclaims rather than by the foregoing description.

1. A chromophore of the formula

wherein A=H or CH₃; X═O or NH; n=2-6; m=0-6; R¹═H, OH, C₁-C₄ alkyl, orC₁-C₄ alkoxy; and R²═H or OH.
 2. The chromophore of claim 1 whereinA=CH₃; X═O; n=2; m=0; R¹═H; and R²═H.
 3. An ophthalmic device materialcomprising the chromophore of claim 1 and a device-forming monomerselected from the group consisting of acrylic monomers andsilicone-containing monomers.
 4. The ophthalmic device material of claim3 wherein the ophthalmic device material comprises from 0.1 to 5% (w/w)of the chromophore.
 5. The ophthalmic device material of claim 4 whereinthe ophthalmic device material comprises from 0.5 to 3% (w/w) of thechromophore.
 6. The ophthalmic device material of claim 3 wherein theophthalmic device material comprises a device-forming monomer of formula[II]:

where in formula [II]: A is H, CH₃, CH₂CH₃, or CH₂OH; B is (CH₂)_(m) or[O(CH₂)₂]_(z); C is (CH₂)_(w); m is 0-6; z is 1-10; Y is nothing, O, S,or NR′, provided that if Y is O, S, or NR′, then B is (CH₂)_(m); R′ isH, CH₃, C_(n′)H_(2n′+1) (n′=1-10), iso-OC₃H₇, C₆H₅, or CH₂C₆H₅; w is0-6, provided that m+w≦8; and D is H, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₆H₅,CH₂C₆H₅ or halogen.
 7. The ophthalmic device material of claim 6 whereinin formula [II]: A is H or CH₃; B is (CH₂)_(m); m is 1-5; Y is nothingor O; w is 0-1; and D is H.
 8. The ophthalmic device material of claim 7wherein the ophthalmic device material comprises a monomer selected fromthe group consisting of: benzyl methacrylate; 2-phenylethylmethacrylate; 4-phenylbutyl methacrylate; 5-phenylpentyl methacrylate;2-benzyloxyethyl methacrylate; and 3-benzyloxypropyl methacrylate; andtheir corresponding acrylates.
 9. The ophthalmic device material ofclaim 3 wherein the ophthalmic device material comprises a cross-linkingagent.
 10. An intraocular lens comprising the chromophore of claim 1.11. An ophthalmic device comprising the ophthalmic device material ofclaim
 3. 12. The ophthalmic device of claim 11 wherein the ophthalmicdevice is selected from the group consisting of an intraocular lens; acontact lens; a keratoprosthesis; and a corneal inlay or ring.